Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008. / Includes bibliographical references (p. 82-92). / The practical viability of biomolecule-nanostructure hybrids depends critically on the functional and structural stability of biomolecules in application environments. Noncovalent interactions of biochemical functional groups with nanostructure surfaces can significantly disrupt biomolecular structure and function. We report a systematic study of the effect of DNA sequence on the binding interaction between gold nanoparticles and thiolated DNA (AuNp-DNA). Base specific noncovalent nucleotide adsorption on gold surfaces can affect nucleotide bioavailability in solution. Systematic investigation of DNA oligonucleotide sequence, the location of specific sequence motifs, and the effect of nanoparticle size was performed. Sequence effects on DNA coverage and oligonucleotide adsorption affinities.were studied by Langmuir isotherm analysis. The nanoparticle coverage at saturating concentrations of thiolated DNA varied with oligonucleotide sequence. Saturation coverages correlated well with complement hybridization efficiency. From this we concluded that noncovalent interactions between nucleotides and the particle surface effect both hybridization and DNA coverage and adsorption. This hypothesis was confirmed by chemical treatment of the particle surface to eliminate noncovalent interactions. Upon treatment the effect of sequence on hybridization efficiency was removed. The effect of sequence is not consistent across nanoparticle sizes. Different bases show the highest saturation coverages and hybridization efficiencies on different AuNp sizes. These results allow for sequence selection guidelines based on AuNp size for sizes ranging from 4-11nm. For smaller particles (<5nm) adenine rich sequences show the highest saturation coverage and hybridization efficiency. / (cont.) For mid-sized particles (~7.5nm), guanine sequences show the highest saturation coverage and hybridization efficiency. Larger particles (>10nm) show little sequence dependent behavior and are likely the best choice for uses where sequence choice is limited. Sequence selection based on these guidelines will provide AuNp-DNA conjugates with the highest possible oligonucleotide bioavailability, maximizing their utility in biotechnology applications. / by Katherine A. Brown. / Ph.D.

Thesis (S.M. in Technology and Policy)--Massachusetts Institute of Technology, Engineering Systems Division, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 111-122). / As the number of vehicles in China has relentlessly grown in the past decade, the energy demand, fuel demand and greenhouse gas emissions associated with these vehicles have kept pace. This thesis presents a model to project future energy demand, fuel demand and carbon dioxide emissions for the Chinese light duty vehicle fleet. Results indicate that China can offset rapid vehicle energy demand growth with reductions in fuel consumption and new vehicle technologies. These reference scenario results indicate that future light duty vehicle energy demand and carbon dioxide emissions will peak below 400 mtoe and 1700 mmt carbon dioxide, respectively. In addition, a scenario based sensitivity analysis reveals that vehicle stock, vehicle fuel consumption and vehicle fleet electrification are the most significant drivers in determining future light duty vehicle energy demand, fuel demand and carbon dioxide emissions. The Chinese government is concerned with these trends. In a complementary analysis, I investigate existing government policy strategies that may affect future automotive energy demand. I find that policy strategies are fairly well aligned with the significant drivers to reduce automotive energy demand. However, I also find that national government policies are often not implemented as intended at the local government level. Finally, I analyze current domestic and joint venture brand vehicle technology, where I find that domestic car technology lags joint venture car technology. / by Ingrid Gudrun Bonde Åkerlind. / S.M.in Technology and Policy

Thesis (Ph. D.)--Massachusetts Institute of Technology, Engineering Systems Division, 2006. / Includes bibliographical references (p. 216-230). / Large engineering projects design, engineer and construct much of the world's energy, transportation and defense infrastructure. These large scale engineering endeavors are highly visible, have long lasting impacts and are of major economic significance. Yet despite their importance they frequently suffer from cost overruns and long delays and deliver systems with operational shortcomings. A contributing factor to the challenge of large projects is that the project enterprise is created by separate firms being brought together by the project sponsor, typically via formal contracts. Success requires multiple firms with hundreds (possibly thousands) of engineers working together to efficiently create complex product systems within an environment of high uncertainty. In an attempt to improve project outcomes, sponsors often endeavor to create "alignment" between themselves and their key contractors. In practice, alignment has proved difficult to create and to sustain. This research explores the policies and actions taken by firms that give rise to alignment. The large engineering projects studied for this research were offshore oil and gas field developments. grounded theory method, supplemented by formal dynamic model building, was used to investigate the causal mechanisms that support, or inhibit, the generation of alignment. The research revealed that alignment is founded on the collective understanding of the project, incorporating the firm's separate interests, and inter-firm trust. Furthermore the two antecedents of alignment act together to form a self-enforcing alignment mechanism. Six factors (system architecture, organizational design, contract design, risk, metrics and incentives) were identified that establish the inter-firm interactions through which collective understanding and inter-firm trust are created. These findings are organized into a framework that guides policy selection with a view to enabling the generation, and sustainment, of alignment. / (cont.) A grounded theory method, supplemented by formal dynamic model building, was used to investigate the causal mechanisms that support, or inhibit, the generation of alignment. The research revealed that alignment is founded on the collective understanding of the project, incorporating the firm's separate interests, and inter-firm trust. Furthermore the two antecedents of alignment act together to form a self-enforcing alignment mechanism. Six factors (system architecture, organizational design, contract design, risk, metrics and incentives) were identified that establish the inter-firm interactions through which collective understanding and inter-firm trust are created. These findings are organized into a framework that guides policy selection with a view to enabling the generation, and sustainment, of alignment. / by Nicholas McKenna. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006. / Includes bibliographical references. / Ex vivo expansion of hematopoietic stem cells (HSCs) is a long-standing challenge faced by both researchers and clinicians. To date, no robust, efficient method for the pure, ex vivo expansion of human HSCs has been demonstrated. Previous methods primarily induced the expansion of committed hematopoietic progenitor cells (HPCs), yielding even less pure populations of HSCs. This research was based on the hypothesis that, like for other adult stem cells (ASCs), the major barrier to expanding HSCs ex vivo is in preferentially regulating the asymmetric self-renewal of HSCs without loss in their ability to produce differentiated committed HPCs. This laboratory has shown that a p53-dependent pathway specifically controls the self-renewal pattern of several types of ASCs and thereby provides an effective means for expansion of ASCs in culture. The method, which involves the use of purine metabolites to achieve suppression of asymmetric cell kinetics, is referred to as SACK. The utility of the p53-dependent pathway was investigated for directing expansion of human HSCs. In order to support this investigation, the proliferation of HPCs in in vitro cultures was repressed by culturing cells without hematopoietic growth factors and cytokines. / (cont.) This allowed the in vitro detection of SACK-effects on a small sub-population of cells, predicted to include HSCs. In order to determine the self-renewal capacity and multilineage potential of SACK- cultured cells, they were transplanted into non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. In vivo transplantation investigations exhibited 1.9- fold to 4.5-fold increased engraftment efficiency with SACK-agents compared to SACK-free controls, suitable for clinical applications. This result suggests that SACK-culture expands a population of SCID-repopulating cells (SRCs) that yields self-renewal and multilineage engraftment in NOD/SCID mice. Accordingly, increased engraftment efficiency for successful clinical applications may be achieved after additional optimization of HSC expansion. To obtain the full therapeutic potential of expanded HSCs, development of methods for independently marking putative ASCs for future analyses and gene therapy was explored. This early success with human HSCs supports the basic hypothesis that the SACK approach may be applicable to expansion of many types of ASCs. / by Rouzbeh R. Taghizadeh. / Ph.D.

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2005. / Includes bibliographical references (leaves 95-96). / This thesis is a part of the Supply Chain 2020 research project which seeks to study best practices in supply chain management in multiple industries in order to develop a deeper understanding of key principles and practices characterizing the creation of excellent supply chains through a long-term research agenda. This thesis addresses the first phase of the research by concentrating on the aerospace industry and by focusing on Rolls-Royce through a case study. The objective of the thesis is to conduct an exploratory study of the best practices in supply chain management in the aircraft engine manufacturing industry, and how these practices impact the competitive positioning of an engine manufacturer within the industry. The analysis involves a broad review of the current state and future directions of the aerospace industry by tracing the key factors shaping its evolution and by identifying the major strategic forces that would influence its future. Within this general industry context, the thesis analyzes Rolls-Royce's position in the industry as a leading aircraft engine manufacturer and presents a focused study of Rolls-Royce's supply chain management practices. / (cont.) In particular, the thesis involves a deeper exploration of the aircraft engine manufacturing business segment of Rolls-Royce and strives to understand the company's supply chain management practices, by examining the role of major factors that have proven crucial to effective supply chain management within the company. The thesis also presents more specific case study examples that track the implementation and results of major supply chain management initiatives. Finally, the supply chain design and management practices are analyzed from the perspective of their role in the company's business strategy. This is accomplished by employing a number of business strategy frameworks to understand the key factors that determine the competitiveness of a tier one supplier in the aerospace industry, such as Rolls- Royce, and by examining how those factors have affected Rolls-Royce's supply chain management strategies and practices. / by Mohit Tiwari. / M.Eng.in Logistics

Thesis (Ph. D.)--Massachusetts Institute of Technology, Engineering Systems Division, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 223-232). / Systems Theoretic Process Analysis (STPA) is a powerful new hazard analysis method designed to go beyond traditional safety techniques-such as Fault Tree Analysis (FTA)-that overlook important causes of accidents like flawed requirements, dysfunctional component interactions, and software errors. Although traditional techniques have been effective at analyzing and reducing accidents caused by component failures, modem complex systems have introduced new problems that can be much more difficult to anticipate, analyze, and prevent. In addition, a new class of accidents, component interaction accidents, has become increasingly prevalent in today's complex systems and can occur even when systems operate exactly as designed and without any component failures. While STPA has proven to be effective at addressing these problems, its application thus far has been ad-hoc with no rigorous procedures or model-based design tools to guide the analysis. In addition, although no formal structure has yet been defined for STPA, the process is based on a control-theoretic framework that could be formalized and adapted to facilitate development of automated methods that assist in analyzing complex systems. This dissertation defines a formal mathematical structure underlying STPA and introduces a procedure for systematically performing an STPA analysis based on that structure. A method for using the results of the hazard analysis to generate formal safety-critical, model-based system and software requirements is also presented. Techniques to automate both the STPA analysis and the requirements generation are introduced, as well as a method to detect conflicts between safety requirements and other functional model-based requirements during early development of the system. / by John P. Thomas IV. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2004. / Includes bibliographical references. / Biological cells such as endothelial or muscle cells respond to mechanical stimulation with activation of specific intracellular and extracellular signaling pathways and cytoskeletal remodeling, a process termed mechanotransduction. Intracellular mechanosensors are thought to be activated by conformational changes induced by local cellular deformations. Since these mechanosensors have been speculated to be located in several cellular domains including the cell membrane, the cytoskeleton, and the nucleus, it is necessary to achieve a detailed understanding of subcellular mechanics. In this work, we present novel methods to independently quantify cytoskeletal displacements, mechanical coupling between the cytoskeleton and the extracellular matrix, and nuclear mechanics based on high resolution tracking of cellular structures and receptor bound magnetic beads in response to applied strain or microscopic forces. These methods were applied to study the effects of several human disease associated mutations on subcellular mechanics and to examine the interaction between known protein function and specific changes in cellular mechanical properties and mechanotransduction pathways. Initial experiments were targeted to the role of membrane adhesion receptors. Experiments with cells expressing a mutant form of the integrin-associated molecule tetraspanin CD151 revealed that CD151 plays a key role in selectively strengthening α6βl integrin-mediated adhesion to laminin-1. We then studied cytoplasmic behavior using cells from mice with an αB-Crystallin mutation (R120G) that causes desmin-related myopathy. These studies showed impaired passive cytoskeletal mechanics in adult mouse cardiac myocytes. Finally, we studied cells deficient in the nuclear envelope / (cont.) protein lamin A/C and showed that lamin A/C deficient cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain, suggesting that the tissue specific effects observed in laminopathies such as Emery-Dreifuss muscular dystrophy or Hutchinson-Gilford progeria may arise from varying degrees of impaired nuclear mechanics and transcriptional regulation. In conclusion, our methods provide new and valuable tools to examine the role of subcellular biomechanics on mechanotransduction in normal and mutant cells, leading to improved understanding of disease mechanisms associated with altered cell mechanics. / by Jan Lammerding. / Ph.D.

Thesis (S.M.)--Massachusetts Institute of Technology, Engineering Systems Division, 2006. / Includes bibliographical references (p. 93-94). / The purpose of this research is to discuss employment in the United States (US) service sector. The main concern is not pinpointing numerical estimates, but instead identifying trends which lead to job growth or job loss. Like manufacturing jobs that have been lost to offshore locations or productivity gains, so too are service jobs at risk. Offshoring - the outsourcing of business functions overseas - and automation have the same effect of displacing workers. What keeps a service job in the US and what makes it ideal to ship overseas or replace with a computer? Consumers have several choices between different product and service offerings. And, different products need varied levels of aftermarket service. What makes customers go out and spend money rather than completing tasks themselves? This thesis attacks these questions by outlining characteristics of products, services, and consumers which could help label jobs as "safe" or "at-risk." First is a discussion of these characteristics. Then, the range of product and service alternatives that consumers have to choose from is presented and applied to examples. / (cont.) Overall, jobs which may be at-risk are those occupations that can be offshored, automated, or easily performed by consumers themselves. On the other hand, jobs that may prove safer are those with high barriers to self-service, those that offer a customized service or experience, and those that require physical contact to be performed. / by Eric D. Gorney. / S.M.

Thesis (M. Eng. in Logistics)--Massachusetts Institute of Technology, Engineering Systems Division, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 78-79). / This thesis involves railcar fleet sizing strategies with a specific company in the chemical industry. We note that the identity of the company in this report has been disguised, and some portions of the fleets have been omitted to mask their actual sizes. However, all analysis in this thesis was conducted on actual data. In our research, we evaluate the appropriateness of both deterministic and stochastic fleet sizing models for this company. In addition, we propose an economic model that is adapted from a basic inventory management policy that can be applied to fleet sizing in order to arrive at a cost-driven solution. Through our research, we demonstrate that the fleet sizing strategy of this company can be improved by incorporating transit time variability into the fleet sizing model. Additionally, we show that fleet sizes can be reduced by accurately characterizing the distributions of the underlying transit and customer holding time data. Finally, we show the potential value of considering economic factors to arrive at a fleet sizing decision that balances the cost of over-capacity with the cost of an insufficient supply of railcars. / by Jay Jagatheesan and Ryan Kilcullen. / M.Eng.in Logistics

Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006. / Includes bibliographical references. / Endogenous and exogenous oxidants react with cellular macromolecules to generate a variety of electrophiles that react with DNA produce cytotoxic and mutagenic adducts. One source of such electrophiles is deoxyribose in DNA itself. Oxidation of each position in deoxyribose generates a unique spectrum of products, many of which are highly reactive with DNA bases and lead to formation of adducts. The objective of this thesis was to clarify the chemistry of deoxyribose oxidation, with a focus on C4'-oxidation that gives rise to 3'- phosphoglycolate residues on the DNA backbone and releases base propenal or malondialdehyde, and to investigate the role of base propenals in the formation of an important endogenous DNA adduct, MI dG. First, an index of total deoxyribose oxidation was developed, one that provides a means to compare different oxidizing agents. This method exploits the reaction of aldehyde- and ketone-containing deoxyribose oxidation products with 14C-methoxyamine to form stable oxime derivatives that are quantified by accelerator mass spectrometry. Sensitive GC/MS methods were developed to quantify 3'-phosphoglycolate residues from deoxyribose C4'-oxidation and HPLC/post-column derivatization methods were developed to quantify the corresponding base propenal or malondialdehyde. / (cont.) Combined with the quantification of total deoxyribose oxidation and the alternative product of C4'-oxidation, the 4'-ketoaldehyde abasic site, under the same conditions, these results offered direct insights into the partitioning of C4'-oxidation and the chemical mechanisms of deoxyribose oxidation in DNA. With a foundation of deoxyribose oxidation chemistry and analytical methods, the in vitro DNA oxidative damage induced by y-irradiation, Fe2+/EDTA, bleomycin and peroxynitrite was explored. The results revealed that malondialdehyde was neither sufficient nor necessary for the formation of MldG, while base propenal was effective in generating MldG. These observations were extended to an E. coli cell model in which the membrane content of polyunsaturated fatty acids was controlled. The results revealed that lipid peroxidation caused by y-irradiation was insufficient to produce MldG in cells and the level of MldG adducts was inversely correlated with the quantity of membrane polyunsaturated fatty acids when cells were treated with peroxynitrite. Finally, M1dG showed a moderate (-50%) increase in tissues from a mouse model of inflammation, while etheno-adducts induced by lipid peroxidation increased -3- fold. These results are again consistent with lipid peroxidation as a minor source of MldG. / by Xinfeng Zhou. / Ph.D.